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首页> 外文期刊>Molecular and Cellular Biology >Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1.
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Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1.

机译：通过特异性抑制Stat1的酪氨酸去磷酸化来增强γ干扰素的抗增殖活性。

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摘要

Gamma interferon (IFN-gamma) signals to the nucleus through the activation, by tyrosine phosphorylation, of the latent cytoplasmic transcription factor Stat1 (signal transducer and activator of transcription). It has been demonstrated that the activity of Stat1 is dependent on tyrosine phosphorylation which is regulated by Jak tyrosine kinases as well as by the as-yet-unidentified protein tyrosine phosphatase. We report that the N-terminal domain of Stat1, which is highly conserved among all STAT family members, is required for its tyrosine dephosphorylation. A single amino acid substitution (Arg-31 to Ala) in the Stat1 N-terminal domain inhibited Stat1 tyrosine dephosphorylation. The deletion of the Stat1 N-terminal domain resulted in a mutant Stat1 protein which was constitutively phosphorylated on Tyr-701. Upon IFN-gamma stimulation, the tyrosine phosphorylation of this mutant protein was further enhanced but was not down-regulated by protein tyrosine phosphatase in vivo. When expressed in NIH 3T3 cells, this mutant protein greatly enhanced the antiproliferative activity of IFN-gamma. We suggest that the N-terminal domains of STATs are crucial for modulating STAT activities through regulating the tyrosine dephosphorylation of STATs.
机译：γ干扰素（IFN-γ）通过酪氨酸磷酸化激活潜伏的细胞质转录因子Stat1（信号转导子和转录激活子），从而向细胞核发出信号。已经证明Stat1的活性取决于酪氨酸磷酸化，酪氨酸磷酸化由Jak酪氨酸激酶以及迄今尚未鉴定的蛋白酪氨酸磷酸酶调节。我们报告说，Stat1的N末端结构域在所有STAT家族成员中高度保守，是其酪氨酸脱磷酸作用所必需的。 Stat1 N末端域中的单个氨基酸取代（从Arg-31到Ala）抑制了Stat1酪氨酸的去磷酸化。 Stat1 N末端结构域的删除导致突变Stat1蛋白在Tyr-701上被组成性磷酸化。在IFN-γ刺激下，该突变蛋白的酪氨酸磷酸化进一步增强，但在体内没有被蛋白酪氨酸磷酸酶下调。当在NIH 3T3细胞中表达时，这种突变蛋白大大增强了IFN-γ的抗增殖活性。我们建议STATs的N末端域对于通过调节STATs的酪氨酸去磷酸化来调节STAT活性至关重要。

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